title: The human melanoma side population displays molecular and functional characteristics of enriched chemoresistance and tumorigenesis.
abstract: Melanoma remains the most lethal skin cancer, mainly because of high resistance to therapy. Side population (SP) cells are found in many types of cancer and are usually enriched in therapy-resistant as well as tumorigenic cells. Here, we identified a Hoechst dye-effluxing SP in a large series of human melanoma samples representing different progression phases. The SP size did not change with disease stage but was correlated with the prognostic "Breslow's depth" in the primary (cutaneous) tumors. When injected into immunodeficient mice, the SP generated larger tumors than the bulk "main population" (MP) melanoma cells in two consecutive generations, and showed tumorigenic capacity at lower cell numbers than the MP. In addition, the SP reconstituted the heterogeneous composition of the human A375 melanoma cell line, and its clonogenic activity was 2.5-fold higher than that of the MP. Gene-expression analysis revealed upregulated expression in the melanoma SP (versus the MP) of genes associated with chemoresistance and anti-apoptosis. Consistent with these molecular characteristics, the SP increased in proportion when A375 cells were exposed to the melanoma standard chemotherapeutic agent dacarbazine, and to the aggravating condition of hypoxia. In addition, the SP showed enhanced expression of genes related to cell invasion and migration, as well as to putative (melanoma) cancer stem cells (CSC) including ABCB1 and JARID1B. ABCB1 immunoreactivity was detected in a number of tumor cells in human melanomas, and in particular in clusters at the invasive front of the primary tumors. Together, our findings support that the human melanoma SP is enriched in tumorigenic and chemoresistant capacity, considered key characteristics of CSC. The melanoma SP may therefore represent an interesting therapeutic target.
authors.affiliation: Translational Cell & Tissue Research, Dept. of Imaging and Pathology, University of Leuven (KU Leuven), Leuven, Belgium ; Research Unit of Stem Cell Research (Lab. of Tissue Plasticity), Cluster Stem Cell Biology and Embryology, Dept. of Development and Regeneration, University of Leuven (KU Leuven), Leuven, Belgium.
authors.forename: Jasper
authors.initials: J
authors.lastname: Wouters
authors.forename: Marguerite
authors.initials: M
authors.lastname: Stas
authors.forename: Lies
authors.initials: L
authors.lastname: Gremeaux
authors.forename: Olivier
authors.initials: O
authors.lastname: Govaere
authors.forename: Anke
authors.initials: A
authors.lastname: Van den Broeck
authors.forename: Hannelore
authors.initials: H
authors.lastname: Maes
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Joost J
authors.initials: JJ
authors.lastname: van den Oord
authors.forename: Hugo
authors.initials: H
authors.lastname: Vankelecom
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003606:Dacarbazine / Q000494:pharmacology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D003606:Dacarbazine; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human